Scleroderma, or fibrosis of the skin, is a disease caused by a surplus of extracellular matrix protein localized in the skin, or it may become systemic (systemic sclerosis) with excess collagen collecting in the kidneys, lungs, gastrointestinal tract, and heart. Scleroderma affects approximately 400,000 people in the United States every year. There is no known cure for scleroderma and the exact cause remains unknown. Treatment is currently limited to management of symptoms in order to improve quality of life and limit long-term complications. Common treatments for scleroderma include anti-fibrotic agents, anti-inflammatory agents, and vasodilators. Immunosuppressive agents such as corticosteroids have demonstrated only marginal efficacy.
The exact cause of scleroderma is unknown but it is thought to be an autoimmune disease. Several studies have shown some evidence of geographic clustering, which is also consistent with possible environmental risk factors. A number of international studies suggest that scleroderma occurs much more frequently in the United States than elsewhere. In addition, diffuse scleroderma appears to occur more frequently among African-American women and starts at an earlier age. These regional differences may be a consequence of differential genetic susceptibility to scleroderma, different exposure to possible environmental triggers, or a combination of both. Scleroderma may occur at any age, but the symptoms most frequently begin in mid-life.
The pathophysiology of scleroderma can be localized or general. Localized scleroderma affects the skin, resulting in appearance of morphia, or hard, oval shaped patches that appear white with a purple ring. Additionally, lines or streaks of thickened skin frequently appear in areas such as the arms, legs or forehead. Generalized scleroderma may affect many parts of the body, and is classified into two types, limited and diffuse. Limited scleroderma occurs gradually, and affects the skin and internal organs, such as the esophagus, lungs, and intestines. Diffuse scleroderma develops more suddenly, with skin thickening throughout the body. Further symptoms include ulcers or sores on fingers, loss of hair over affected areas, or swelling or puffiness in the extremities. More extreme symptoms include arthritis, muscle weakness, and heart and lung complications. According to research studies, the total costs of scleroderma in the United States reach $1.5 billion annually. Morbidity represents the major cost burden, associated with $819 million or over 55% of the total costs. The high cost of scleroderma shows that the burden of rare chronic diseases is often high. The elevated costs reflect a young age of disease onset as well as the need for treatments to decrease morbidity costs. Hence there is a critical need for an effective and affordable therapy.
The pathogenesis of fibrosis in scleroderma involves a complex set of interactions between the fibroblast and its surroundings. Multiple fibrotic pathways are activated for reasons that are not completely understood, but involve immune activation, microvascular damage, and fibroblast transformation into the myofibroblast, the main mediator of extracellular collagen accumulation. After an acute injury has healed, differential proliferation and apoptosis preserve the myofibroblast phenotype rather than leading to a selective depletion of activated fibroblasts. Disproportionate fibroblast activity may result from a combination of possible cellular and matrix defects that include fibrillin protein abnormalities, auto-antibody formation, type II immune response, excessive endothelial response to injury, and excessive fibroblast response to TGFβ1. The ubiquitous growth factor TGFβ1 is the most potent protein involved in collagen gene expression and connective tissue accumulation and its role has been well documented. TGFβ1 is capable of inducing its own expression in a variety of cell types, including dermal fibroblasts which produce TGFβ1, indicates the existence of a possible autocrine feedback loop acting in a paracrine manner. Persistent overproduction of collagen and other connective tissue macromolecules results in excessive tissue deposition, and is responsible for the progressive nature of scleroderma. The rapid expansion of knowledge regarding the effects of cytokines on synthesis of the extracellular matrix has led to an appreciation of the enormous complexity of regulatory networks that operate in the physiologic maintenance of connective tissue and which may be responsible for the occurrence of pathologic fibrosis. Numerous other cytokines, as well as cell-matrix interactions, also modify collagen expression and can significantly influence the effects of TGFβ1.
It is towards the treatment of various fibrotic diseases of connective tissue and in particular of the skin that the present invention is directed.